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1.
Chemosphere ; 286(Pt 1): 131683, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34351278

RESUMO

Butachlor being an important member of chloroacetanilide herbicides, is frequently used in agriculture to control unwanted weeds. Exposure to butachlor can induce cancer, human lymphocyte aberration, and immunotoxic effects in animals. The current experimental trial was executed to determine the potential risks of herbicide butachlor to immunotoxicity and its mechanism of adverse effects on the spleen. For this purpose, mice were exposed to 8 mg/kg butachlor for 28 days, and the toxicity of butachlor on the spleen of mice was evaluated. We found that butachlor exposure led to an increase in serum ALB, GLU, TC, TG, and TP and changes in the morphological structure of the spleen of mice. More importantly, results showed that butachlor significantly increased the expression level of ATG-5, decreased the protein expression of LC3B and M-TOR, and significantly decreased the mRNA content of M-TOR and p62. Results revealed that the mRNA contents of APAF-1, CYTC, and CASP-9 related genes were significantly decreased after butachlor treatment. Subsequently, the mRNA levels of inflammatory cytokines (IL-1ß, TNF-α, IL-10) were reduced in the spleen of treated mice. This study suggested that butachlor induce spleen toxicity and activate the immune response of spleen tissue by targeting the CYTC/BCL2/M-TOR pathway and caspase cascading activation of spleen autophagy and apoptosis pathways which may ultimately lead to immune system disorders.


Assuntos
Herbicidas , Acetanilidas , Animais , Apoptose , Autofagia , Herbicidas/toxicidade , Camundongos , Baço
2.
Cancer Lett ; 524: 206-218, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34688842

RESUMO

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Linfoma de Células B/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores de Superfície Celular/genética , Acetanilidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Histona Acetiltransferases/genética , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Camundongos , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Rev Assoc Med Bras (1992) ; 67(12): 1793-1797, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34909951

RESUMO

OBJECTIVE: Ureteral stents usually cause pain and lower urinary tract discomfort. This study aimed to compare the effect of mirabegron with oxybutynin in relieving ureteral stent-related symptoms over time. METHODS: A prospective, longitudinal, randomized, single-blinded study was conducted. Patients who had a ureteral stent inserted after urolithiasis treatment were classified into two groups and received either oxybutynin 5 mg/day (Group O) or mirabegron 50 mg/day (Group M). The Ureteral Stent Symptoms Questionnaire (USSQ) was applied on the 3rd, 6th, and 15th postoperative days. Group domain scores were compared, and a mixed linear model was used to better assess score differences. RESULTS: Ureteral Stent Symptoms Questionnaire scores were similar in both groups during all three postoperative days (p>0.05). A longitudinal analysis showed that global quality of life and general health improved over time, independently of the use of any of the medications (p<0.05), while urinary symptoms and body pain scores were lower over time in participants receiving oxybutynin. CONCLUSION: Both mirabegron and oxybutynin are equivalent in relieving ureteral stent symptoms. Moreover, some stent symptoms seem to decrease over time despite the use of medication.


Assuntos
Qualidade de Vida , Stents , Acetanilidas , Humanos , Ácidos Mandélicos , Estudos Prospectivos , Stents/efeitos adversos , Inquéritos e Questionários , Tiazóis
4.
Pestic Biochem Physiol ; 179: 104970, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34802520

RESUMO

The widespread use of herbicides has raised considerable concern with regard to their harmful consequences on plant growth, crop yield and the soil ecological environment. It has been well documented that colonization of rhizobacteria in the plant root system has a positive effect on activation of plant defenses to protect the plant from damage. Using the platform of high-throughput analysis with tandem mass spectrometry and Illumina sequencing, we identified the specific activated rhizobacteria, the key growth stimulating substances and the metabolic pathways involved in seedling stage tolerance to mefenacet stress in rice. The relative abundance of beneficial rhizospheremicrobes such as Acidobacteria and Firmicutes increased with mefenacet treatment, indicating that the rhizosphere recruited some beneficial microbes to resist mefenacet stress. Mefenacet treatment induced alterations in several interlinked metabolic pathways, many of which were related to activation of defense response signaling, especially the indole-3-pyruvate pathway. Indole-3-acetaldehyde and indole-3-ethanol from this pathway may act as flexible storage pools for indole-3-acetic acid (IAA). Our findings also suggest that a significant increase of IAA produced by the enrichment of beneficial rhizospheremicrobes, for example genus Bacillus, alleviated the dwarfing phenomenon observed in hydroponic medium following mefenacet exposure, which may be a key signaling molecule primarily for phytostimulation and phytotolerance in microbe-plant interactions.


Assuntos
Oryza , Rizosfera , Acetanilidas , Benzotiazóis , Raízes de Plantas , Microbiologia do Solo
5.
Medicine (Baltimore) ; 100(41): e27469, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731124

RESUMO

BACKGROUND: We conducted this meta-analysis to explore the tolerance of monotherapy with mirabegron (50 mg) on an overactive bladder, compared with a common dosage of anticholinergic agents. MATERIALS AND METHODS: A comprehensive search for all randomized controlled trials that evaluated the safety of mirabegron and anticholinergic agents on overactive bladder was performed, and we searched the Cochrane Central Register of Controlled trials databases, Pubmed, Embase, and relevant trials from 2013.02 to 2019.10. RESULTS: Eight studies included 5500 patients with treatment of monotherapy on overactive bladder were identified. The total number of treatment-emergent adverse events had no significantly difference between two monotherapies (RR = 0.88 95%CI: 0.76-1.01; P = .08); however, patients would have a better tolerance with mirabegron (50 mg) in adverse events of dry mouth (RR = 0.42; 95%CI: 0.33-0.53; P < .01) and tachycardia (RR = 0.52; 95%CI: 0.29-0.94; P = .03); and there were no significant differences between two groups in hypertension (RR = 1.02; 95%CI: 0.80-1.30; P = .90), constipation (RR = 0.91; 95%CI: 0.65-1.26; P = 0.57), blurred vision (RR = 1.03; 95%CI: 0.60-1.77; P = 0.92), and urinary tract infection (RR = 0.90; 95%CI: 0.70-1.16; P = .41). CONCLUSIONS: Treatment-emergent adverse events in patients with overactive bladder who underwent monotherapy of mirabegron (50 mg) or the anticholinergic agents had no significant differences, but mirabegron has a better tolerance in the aspect of dry mouth and tachycardia.


Assuntos
Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Antagonistas Colinérgicos/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/epidemiologia , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Taquicardia/induzido quimicamente , Taquicardia/epidemiologia , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Infecções Urinárias/induzido quimicamente , Infecções Urinárias/epidemiologia , Baixa Visão/induzido quimicamente , Baixa Visão/epidemiologia , Xerostomia/induzido quimicamente , Xerostomia/epidemiologia
6.
BMJ Open ; 11(9): e049858, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34588252

RESUMO

INTRODUCTION: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the ß3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating ß3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. METHODS AND ANALYSIS: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. ETHICS AND DISSEMINATION: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes. TRIAL REGISTRATION NUMBER: ACTRN12619000423112; Results.


Assuntos
Doença Arterial Periférica , Receptores Adrenérgicos beta 3 , Acetanilidas , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Humanos , Estudos Multicêntricos como Assunto , Doença Arterial Periférica/tratamento farmacológico , Desempenho Físico Funcional , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis , Caminhada
7.
Rev Assoc Med Bras (1992) ; 67(5): 713-717, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34550261

RESUMO

OBJECTIVE: Stress-type and urgency-type urinary incontinence are seen together in mixed-type urinary incontinence. Treatment is usually chosen according to the predominant type of incontinence. The aim of this study is to evaluate the effect of mirabegron and duloxetine combination in the treatment of mixed-type urinary incontinence. METHODS: The data of 88 mixed-type urinary incontinence patients who applied to the urology outpatient clinic between January 2018 and December 2019 were retrospectively analyzed. We applied mirabegron and duloxetine treatment to the patients. The International Consultation of Incontinence Questionnaire-Short Form, Overactive bladder symptom score questionnaire and daily pad count were statistically evaluated before and after the treatment. RESULTS: Statistically significant improvements were observed using the questionnaire forms and decreased daily pad usage after the eight-week treatment (p<0.001). Based on the clinical global effect scale, 62.50% of patients had a partial or complete response to treatment and also the use of daily pads were decreased from 3.7-0.89 on an average. CONCLUSION: Combination use of mirabegron and duloxetine in the treatment of mixed-type urinary incontinence improved symptom scores and decreased pad usage.


Assuntos
Bexiga Urinária Hiperativa , Incontinência Urinária , Acetanilidas , Método Duplo-Cego , Cloridrato de Duloxetina/uso terapêutico , Humanos , Estudos Retrospectivos , Tiazóis , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico
8.
BMC Cancer ; 21(1): 1061, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565342

RESUMO

BACKGROUND: Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. METHODS: Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses. RESULTS: Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy. CONCLUSIONS: Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.


Assuntos
Acetanilidas/farmacologia , Azepinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazóis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Esferoides Celulares/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
9.
Adv Ther ; 38(11): 5452-5464, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34537953

RESUMO

BACKGROUND: In the absence of head-to-head trials, we performed an indirect treatment comparison of the ß3-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB). METHODS: PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively. RESULTS: After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials. CONCLUSIONS: Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.


Assuntos
Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3 , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Humanos , Antagonistas Muscarínicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico
10.
Neurourol Urodyn ; 40(8): 2041-2047, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34516666

RESUMO

OBJECTIVES: To evaluate the neurological safety and clinical efficacy of darifenacin and mirabegron in patients with a history of cerebrovascular accident (CVA) who had overactive bladder (OAB) symptoms. METHODS: This prospective randomized study, approved by the institute's ethics committee, was carried out at a tertiary care center from December 2018 to June 2020. Treatment naïve adult patients with a past history of CVA with stable neurological status for atleast past 3 months with symptoms of OAB for 3 or more months were included. Eligible patients received either darifenacin or mirabegron for a period of 3 months and various parameters on the 3-day International Consultation on Incontinence Questionnaire (ICIQ) bladder diary, the Montreal Cognitive Assessment-Basic score (MoCA-B), and the adverse events at 3 months posttreatment were compared to that at the baseline. RESULTS: A total of 60 patients were included, 30 in each arm. After 3 months of treatment with darifenacin or mirabegron, the majority of the ICIQ bladder diary parameters improved and there was no deterioration in the cognitive function as noted on the MoCA-B score in either of the arms. On intergroup comparison, the mean change in bladder diary parameters and the MoCA-B scores was similar between the two groups. CONCLUSION: Darifenacin and mirabegron, in the short term, do not adversely affect the cognitive function in patients with a history of CVA with OAB symptoms. Both are safe and effective treatment options in patients with OAB post-CVA.


Assuntos
Acidente Vascular Cerebral , Bexiga Urinária Hiperativa , Agentes Urológicos , Acetanilidas/efeitos adversos , Adulto , Benzofuranos , Humanos , Estudos Prospectivos , Pirrolidinas , Tiazóis , Resultado do Tratamento , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/efeitos adversos
11.
Neurourol Urodyn ; 40(8): 1972-1980, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34486168

RESUMO

AIMS: To descriptively evaluate treatment persistence among adults who received mirabegron or antimuscarinics in South Korea. METHODS: This study involved a retrospective analysis of the Health Insurance Review and Assessment (HIRA) database. Patients (≥18 years) who had a new prescription for an overactive bladder (OAB) target medication (mirabegron/antimuscarinic) within an 8-month index period (July 1, 2015-February 29, 2016) were included. The date when the target (index) medication was dispensed was the index date. The 6-month period before the index date was used to assess patient eligibility. A 12-month post-index period was used to assess medication persistence, which was defined as the time to discontinuation. Overall data were analyzed and the results were also stratified by age group (≤65, >65 years), sex, or prior OAB medication experience. Persistence rates were calculated after the 1st, 3rd, 6th, 9th, and 12th months. RESULTS: A data set of 52 722 cases was obtained (mirabegron: 11 424, antimuscarinics: 41 298). The mean age was 60.9 ± 16.1 years and the majority of the patients were female (30 862 [58.5%] patients). Median persistence was longer with mirabegron (51 days) versus antimuscarinics (25 days). The persistence rate with mirabegron was higher throughout the study compared with all the antimuscarinics (12-month data: 13.5% and 4.9%, respectively). Longer treatment persistence was noted in older, male, and treatment-experienced patients. CONCLUSION: The results from the HIRA database showed that persistence was longer with mirabegron than with antimuscarinics in South Korea. This finding may help inform clinical decision-making within the South Korean healthcare system.


Assuntos
Bexiga Urinária Hiperativa , Agentes Urológicos , Acetanilidas/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/uso terapêutico , República da Coreia , Estudos Retrospectivos , Tiazóis , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/uso terapêutico
12.
Sci Rep ; 11(1): 17495, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471171

RESUMO

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (ß3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the ß3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, ß3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the ß3-AR.


Assuntos
Acetanilidas/farmacologia , Cardiomiopatias/tratamento farmacológico , Losartan/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Insuficiência Renal Crônica/complicações , Tiazóis/farmacologia , Uremia/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Masculino , Nefrectomia/efeitos adversos , Óxido Nítrico Sintase Tipo III/genética , Ratos , Ratos Wistar , Uremia/etiologia , Uremia/metabolismo , Uremia/patologia
13.
Drugs Today (Barc) ; 57(8): 507-517, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34405208

RESUMO

Overactive bladder (OAB) is an extremely common condition in adults of both sexes. It is characterized by an urgent need to micturate often accompanied by incontinence. The condition may also increase the number of micturitions in a 24-hour period as well as nocturia. The syndrome is not due to a urinary infection or other obvious pathology. In terms of drug treatment of OAB, there are two main approaches. One is the use of anticholinergic drugs that reduce the effect of the parasympathetic nervous system on the bladder. The other involves the use of drugs that are agonists at ß3-adrenergic receptors in the bladder. These drugs increase the capacity of the bladder and cause reductions in the number of daily micturitions and nocturia and also importantly reduce the frequency of urinary urgency and urinary urgency incontinence. Vibegron is the second ß3-adrenergic agonist to be approved for the treatment of OAB.


Assuntos
Bexiga Urinária Hiperativa , Acetanilidas , Agonistas Adrenérgicos , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pirimidinonas , Pirrolidinas , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico
14.
Biomolecules ; 11(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439832

RESUMO

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.


Assuntos
Cálcio/metabolismo , Gânglios Espinais/metabolismo , Prurido/genética , Células Receptoras Sensoriais/metabolismo , Canal de Cátion TRPA1/genética , Canais de Cátion TRPV/genética , Acetanilidas/farmacologia , Animais , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Expressão Gênica , Histamina/administração & dosagem , Masculino , Metilistaminas/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imagem Molecular , Cultura Primária de Células , Prurido/induzido quimicamente , Prurido/tratamento farmacológico , Prurido/metabolismo , Purinas/farmacologia , Rutênio Vermelho/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
15.
Invest Ophthalmol Vis Sci ; 62(9): 17, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34241623

RESUMO

Purpose: To determine the effect of the new ß3-agonist (mirabegron), which is used for overactive bladder (OAB) treatment, on central retinal thickness (CRT) and choroidal vascularity. Material and Methods: The 26 eyes of 26 cases using 50 mg tablet mirabegron once per day for OAB were included in this prospective case control study. The CRT, choroidal thickness (ChT), and choroidal vascularity were measured at baseline, week 1 (W1), month 1 (M1), month 2 (M2), and month 3 (M3). Subfoveal ChT measurement included the total subfoveal choroidal thickness (SFCT), and the small and large choroidal vessel layer (SCVL and LCVL) thickness. The total choroidal area (TCA), lumen area (LA), stromal area (SA), stroma/lumen ratio, and choroidal vascularity index (CVI) were measured with the Image-J software. Results: The largest SFCT increase compared to baseline was at M1 (26.8 ± 40.8 µm, P = 0.001). The subfoveal SCVL thickness showed a significant decrease at M2 and M3 (-6.0 ± 8.9 µm, P = 0.002; -7.8 ± 13.4 µm, P = 0.046, respectively). LCVL thickness showed a significant increase at W1, M1, and M2, with the largest at M1. CVI showed a significant increase at M1, M2, and M3 (P < 0.05 for all). The TCA, LA, and SA showed a significant increasing trend at all follow-up periods. LA/SA decreased at W1 because of stromal expansion but increased at M3 with more prominent vascular dilatation. CRT values showed no significant change. Conclusions: Mirabegron had a significant effect on choroidal thickness. Choroidal vascular response is in the form of narrowing in the choriocapillaris and enlargement in the Haller's layer.


Assuntos
Acetanilidas/farmacologia , Corioide/irrigação sanguínea , Vasos Retinianos/efeitos dos fármacos , Tiazóis/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Corioide/diagnóstico por imagem , Corioide/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual
16.
Aktuelle Urol ; 52(4): 312-314, 2021 08.
Artigo em Alemão | MEDLINE | ID: mdl-34318456
17.
Mol Cell ; 81(15): 3205-3215.e5, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34314699

RESUMO

The ß3-adrenergic receptor (ß3AR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type 2 diabetes, obesity, and overactive bladder (OAB). Here, we report the cryogenic electron microscopy structure of the ß3AR-Gs signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported ß1AR and ß2AR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in ß3AR creates a perpendicular pocket for mirabegron. Mutational analyses suggest that a combination of both the exosite shape and the amino-acid-residue substitutions defines the drug selectivity of the ßAR agonists. Our findings provide a molecular basis for ßAR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.


Assuntos
Acetanilidas/química , Agonistas de Receptores Adrenérgicos beta 3/química , Receptores Adrenérgicos beta 3/química , Receptores Adrenérgicos beta 3/metabolismo , Tiazóis/química , Acetanilidas/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Animais , Sítios de Ligação , Microscopia Crioeletrônica , Cães , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Receptores Adrenérgicos beta 3/genética , Tiazóis/metabolismo
18.
Nat Struct Mol Biol ; 28(7): 614-625, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34262183

RESUMO

p97 processes ubiquitinated substrates and plays a central role in cellular protein homeostasis. Here, we report a series of cryo-EM structures of the substrate-engaged human p97 complex with resolutions ranging from 2.9 to 3.8 Å that captured 'power-stroke'-like motions of both the D1 and D2 ATPase rings of p97. A key feature of these structures is the critical conformational changes of the intersubunit signaling (ISS) motifs, which tighten the binding of nucleotides and neighboring subunits and contribute to the spiral staircase conformation of the D1 and D2 rings. In addition, we determined the cryo-EM structure of human p97 in complex with NMS-873, a potent p97 inhibitor, at a resolution of 2.4 Å. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change and thus blocking substrate translocation allosterically.


Assuntos
Trifosfato de Adenosina/química , Dobramento de Proteína , Proteostase/fisiologia , Transdução de Sinais/fisiologia , Proteína com Valosina/metabolismo , Acetanilidas/farmacologia , Animais , Benzotiazóis/farmacologia , Microscopia Crioeletrônica , Retículo Endoplasmático/metabolismo , Degradação Associada com o Retículo Endoplasmático/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Conformação Proteica , Proteínas Ubiquitinadas/metabolismo , Proteína com Valosina/antagonistas & inibidores
19.
Chemosphere ; 283: 131226, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34146870

RESUMO

Butachlor is a systemic herbicide widely applied on wheat, rice, beans, and different other crops, and is frequently detected in groundwater, surface water, and soil. Therefore, it is necessary to investigate the potential adverse health risks and the underlying mechanisms of hepatotoxicity caused by exposure to butachlor in invertebrates, other nontarget animals, and public health. For this reason, a total of 20 mice were obtained and randomly divided into two groups. The experimental mice in one group were exposed to butachlor (8 mg/kg) and the mice in control group received normal saline. The liver tissues were obtained from each mice at day 21 of the trial. Results indicated that exposure to butachlor induced hepatotoxicity in terms of swelling of hepatocyte, disorders in the arrangement of hepatic cells, increased concentrations of different serum enzymes such as alkaline phosphate (ALP) and aspartate aminotransferase (AST). The results on the mechanisms of liver toxicity indicated that butachlor induced overexpression of Apaf-1, Bax, Caspase-3, Caspase-9, Cyt-c, p53, Beclin-1, ATG-5, and LC3, whereas decreases the expression of Bcl-2 and p62 suggesting abnormal processes of apoptosis and autophagy. Results on different metabolites (61 differential metabolites) revealed upregulation of PE and LysoPC, whereas downregulation of SM caused by butachlor exposure in mice led to the disruption of glycerophospholipids and lipid metabolism in the liver. The results of our experimental research indicated that butachlor induces hepatotoxic effects through disruption of lipid metabolism, abnormal mechanisms of autophagy, and apoptosis that provides new insights into the elucidation of the mechanisms of hepatotoxicity in mice induced by butachlor.


Assuntos
Herbicidas , Acetanilidas/toxicidade , Animais , Herbicidas/toxicidade , Metabolismo dos Lipídeos , Fígado , Camundongos
20.
Bioresour Technol ; 337: 125407, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34147771

RESUMO

In this work, Enteromorpha prolifera derived magnetic biochar (MBC) is prepared for the removal of butachlor (BTR) and characterized. The NaOH added during the magnetic loading process has an activating effect and enhancing the accessibility of the pores. Based on the BET result, the importance of pore accessibility rather than the specific surface area has been proposed. The maximum adsorption capacity of BTR for MBC is 158.5 mg/g. Then, the batch experiment shows that the adsorption of MBC to BTR fitted with the quasi-second-order kinetic model. The effect factors on the BTR removal were studied. Through the result of BET, Raman, XPS and FT-IR, the mechanism of MBC adsorption of butachlor was explored. After 3 cycles, the prepared MBC has a negligible reduction in the removal capacity of BTR, which provides a reference scheme for the large-scale application of Enteromorpha prolifera and the water treatment of BTR.


Assuntos
Carvão Vegetal , Poluentes Químicos da Água , Acetanilidas , Adsorção , Cinética , Fenômenos Magnéticos , Espectroscopia de Infravermelho com Transformada de Fourier , Poluentes Químicos da Água/análise
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